Substituted trifluoromethoxy- and tri-



United States Patent 3,133,917 SUBSTITUTED TRIFLUOROMETHOXY- AND TRI- FLUOROMETHYLMERCAPTOPHENOTHIAZINES James W. Wilson, Wayne, Pa., assignor to Smith Kline &

French Laboratories, Phiiadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed May 13, 1959, Ser. No. 812,825 Claims priority, application Great Britain June 3, 1958 14 Claims. (Cl. 260-243) This invention relates to new (dialkylaminoalkyl)- trifluoromethoxyand trifluoromethylmercaptophenothiazines which are useful as therapeutic agents. Further, this invention relates to novel trifluoromethoxyand trifluoromethyhnercaptophenothiazine intermediates.

More specifically, the compounds of this invention have utility as antiemetics, tranquilizers, calmatives, antihistaminics, spasmolytics, antishock agents and potentiators of various central nervous system depressants, such as analgetics or anesthetics. In particular, the compounds are extremely potent antiemetics and have a high degree of activity as tranquilizing agents, coupled with a surprisingly low degree of toxicity. Further, the administration of these compounds to laboratory animals such as dogs has a calmative effect which renders the animals more manageable, particularly during pharmacological testing procedures. In addition, these compounds have chemotherapeutic or antimicrobial activity, such as antibacterial and fungicidal activity. They are particularly active against Micrococcus pyogenes var. aureus, Diplococcus pneumionae Type I, Klebsz'ella pneumoniae, Candida albicans and Hemolytic streptococcus,

and as such are useful in eliminating such infections from animals or from infected laboratory equipment. Certain of the novel compounds of this invention also have utility as intermediates, as will be evident from the following disclosure.

The 10-subst1'tuted phenothiazines of this invention are represented by the general formula:

FORMULA l morpholinyl, piperazinyl or substituted piperazinyl.

The term substituted piperazinyl is used herein to include moieties as represented by the following formula:

FORMULA 2 l a 'M when:

R R R and R represents hydrogen, methyl or ethyl; and

R represents hydrogen, alkyl, acyloxyalkylene such as alkanoyloxyalkylene or monocyclic aroyloxyalkylene such as benzoyloxyalkylene, hydroxyalkylene, dialkylaminoalkylene, hydroxy alkyleneoxyalkylene, phenylalkyl of from 7 to 10 carbons, alicyclicalkyl of from 6 to 10 carbons, or acyl, such as alkanoyl, phenylalkanoyl, alicyclicalkanoyl of from 7 to 10 carbons, monocyclic aroyl, lower carbalkoxy, carbobenzoxy or lower N-substituted carbamyl such as dialkyl carbamyl.

The preferred substituted piperazinyl moieties are N-hydrogen piperazinyl, N-alkylpiperazinyl, N- (w-hydroxyalkylene piper azinyl, N- (w-alkanoyloxyalkylene) -piperazinyl, N- (w-benzoyloxyalkylene) -piperaziny1, N-phenylalkyl-piperazinyl, N-alkanoylpiperazinyl, N,2,3,5,6-pentamethylpiperazinyl and N- (o-hydroxyalkyleneoxyalkylene) -piperazinyl.

The advantageous compounds of this invention are represented by the following formula:

FORMULA 3 YCF3 l z when:

Y represents oxygen or sulfur A represents a divalent, straight or branched alkylene chain containing 2 to 4 carbon atoms separating the nitrogen atoms by at least 2 carbons; and

Z represents dimethylamino, piperazinyl or N-substituted piperazinyl, specifically alkyl, alkanoyloxyethyl, hydroxyethyl or hydroxyalkyleneoxyalkylene piperazinyl.

In the compounds represented by Formulas 1 and 3 above, the YCF group is preferably in the 2 position.

Preferred compounds of this invention are represented by the following formula:

FORMULA 4 YCFB JHz1C!iHCH2Z when:

Y represents sulfur; R represents hydrogen or methyl; and Z represents dimethylamino, N- alkylpiperazinyl, N- acetoxyethylpiperazinyl, N hydroxyethylpiperazinyl or 6 carbon atoms and preferably not more than 4.

This invention also includes salts of the above defined bases formed with nontoxic organic andinonganic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform,

with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, paminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as with the 8-halotheophyllines,

for example 8-bromotheophylline. Examplary of such inlowing synthetic procedure:

FORMULA YCFs YCF; \N \N/ x H l In Formula 5, Y represents oxygen or sulfur and the YCF group is preferably in the 2-position.

'In preparing the lo-unsubstituted phenothiazines, used as intermediates as shown above, the phenothiazine nucleus is readily formed by the thionation of trifiuoromethoxyand trifluoromethylmercaptodiphenyl amines:

In this method, the substituted diphenyl amine is heated with from 1.8 to 2.0 equivalents of sulfur in the presence of a catalytic amount of iodine, for instance from 0.5 to 3.0% by weight of the diphenyl amine. The reaction mixture is advantageously heated at from about 120 to 230 C. for from one-quarter to four hours. The reaction may be run with or without a solvent. Exemplary of suitable, nonreactive organic solvents are xylene or o-dichlorobenzene. Preferably, the reaction mixture is heated without a solvent in an atmosphere of dry nitrogen at from 135 to 175 C. for from about one to two hours. The product is isolated from the reaction mixture by cooling, dissolving the residues in boiling benzene and concentrating the benzene solution. The solid is purified by recrystallization, treatment with activated alumina or vacuum sublimation to give phenothiazine.

The trifluoromethoxyand trifluoromethylmercaptodiphenyl amines are prepared by methods analogous to those in the prior art. For example, 3-bromophenyl methyl sulfide is chlorinated to yield 3-bromophenyl trichloromethyl sulfide which is converted by treatment with antimony trifluori'de to S-bromophenyl trifiuoromethyl sulfide. This compound is then reacted with acetanilide to give 3-trifiuoromethylmercaptodiphenyl amine which is then further reacted as described above.

Alternatively, it is possible to prepare these lO-unsubstituted phenothiazines by the cyclization of substituted diphenyl sulfidesz' YCF3 Yer x NH: g

the nuclear substituted wherein X represents chloro, bromo or iodo and Y is defined as above. This method is carried out by heating the above diphenyl sulfides in the presence of an acidbinding agent, present in at least an amount sufficient to neutralize the hydrohalic acid formed during the reaction. Exemplary of such acid-binding agents are the carbonates, such as sodium carbonate, sodium bicarbonate or preferably potassium carbonate. The reaction is run in a suitable, nonreactive organic solvent in which the reactants are at least partially soluble. Exemplary are dioxane, dimethylaniline, diethylforrn-amide, methylformamide, dimethylformamide or dimethylacetamide. Preferably, the solvent is dimethylformamide and other similar lowercarbon amides.

Optimum yields are obtained when catalytic amounts of copper or copper bronze powder are added, for instance up to 5% by weight of the diphenyl sulfide. The reaction mixture is advantageously heated at from about to 220 C. for long periods, such as from 4 to 60 hours. Preferably, the reaction mixture is heated with stirring at the boiling point of the solvent for from about 8 to 24 hours. The reaction mixture is worked up by cooling, filtering and quenching in water. The separated product is washed, recrystallized and, optionally, sublimed to give the desired substituted phenothiazine.

The substituted trifluoromethoxyand trifiuoromethylmercaptodiphenyl sulfides are prepared by methods analogous to those in the prior art. For instance, 3-nitro-4- chlorophenyl trifiuoromethyl ether (prepared from the nitration of 4-aminophenyl trifiuoromethyl ether and subsequent diazotization) is condensed with o-bromothiophenol under alkaline conditions to give 2-bromo-2-nitro- 4-trifluoromethoxydiphenyl sulfide. The 2-nitro group is reduced with stannous chloride-hydrochloric acid to give 2-bromo 2 amino 4 trifluoromethoxydiphenyl sulfide which is then further reacted as described above.

The intermediate lO-unsubstituted phenothiazines of Formula 5 are alkylated with a reactive dialkylaminoalkyl ester to form the IO-(dialkylaminoalkyl)-trifiuoromethoxyand trifluoromethylmercaptophenothiazines represented by Formula 1. Any reactive dialkylaminoalkyl ester may be used, such as a halide, preferably chloride or bromide, or an aryl sulfonate, preferably p-toluene sulfonate. The reaction is carried out advantageously by refluxing the reactants in a suitable inert aromatic solvent such as, preferably, benzene, toluene or xylene, in which at least one of the reactants must be soluble. A suitable acid-binding agent is usually included, such as an alkali metal amide, preferably sodium, potassium or lithium amide. Other suitable acid-binding agents are alkali metal hydrides, preferably sodium hydride or alkali metal aryl or alkyl compounds, preferably phenyl or octyl sodium. If an acid addition salt of the reactive dialkylaminoalkyl ester is used, a corresponding increase in the amount of acid-binding agent must be used.

The preferred method of alkylation, however, is to react the trifluoromethoxyor trifluoromethylmercaptophenothiazine with a dialkylaminoalkyl chloride or bromide with a slight excess of sodium or potassium amide in refluxing benzene or toluene for from 30 minutes to 36 hours, preferably 3 to 18 hours.

The 10-(dialkylaminoalkyl)-trifiuromethoxyor trifluoromethylmercaptophenothiazine is isolated by cooling the reaction mixture and carefully adding an excess of water. The organic layers are extracted with dilute acid, preferably dilute hydrochloride acid. The acid extracts are combined, neutralized with dilute base and extracted with benzene. The dried benzene extracts are evaporated and the resulting residue is fractionally distilled under high vacuum to give the desired base which is usually a viscous oil and which often may be crystallized, if desired. In practice, the basic oil dissolved in an organic solvent is converted into a stable salt by reacting the solution with a suitable organic or inorganic acid.

The l0-(w-piperazinylalkyl)-trifluoromethoxyand trifluoromethylmercaptophenothiazines are prepared advantageously by alkylating the substituted phenothiazine with an w-haloalkylpiperazine having the free N-hydrogen of the piperazinyl moiety replaced by an easily removed moiety, for example, a benzyl, carbalkoxy, such as carbethoxy, carbobenzoxy, or acyl, such as formyl, group. The N-protective group is then removed under mild conditions, such as by weakly alkaline hydrolysis in the case of the carbethoxy group. The resulting substituted (w-piperazinylalkyl)-phenothiazine is then further alkylated to form various modifications of the compounds of Formula 1 with optional Variations of the moieties of Formula 2. Such methods of alkylation are by a reactive ester, such as an alkylhalide, an aryl sulfonate or a halo substituted alcohol, for example ethylene chlorohydrin, w-bromobutanol or 2-(2'-bromoethoxy)-ethanol, in the presence of an acid-binding agent as described above in an inert solvent such as benzene or xylene; by reaction with an alkylene oxide such as ethylene oxide in a lower alcohol, such as methanol or ethanol; or by reduction of a N-acyl compound such as reduction of the N-acyl analogue with a bimetallic hydride such as lithium aluminum hydride. In addition, 10-(N'-alkyl-N-piperazinylalkyl(-trifiuoromethoxyor trifluoromethylmercaptophenothiazines having a terminal group on the N'-alkyl moiety capable of undergoing reaction are optionally reacted further in the presence of an acid-binding agent to give N'-substituted-alkyl derivatives of 10-(w-piperazinylalkyl)-trifiuoromethoxyor trifluorornethylmercaptophenothiazines. As examples of terminal groups on the N'- alkyl moiety which can be reacted further, an w-hydroxyalkyl is reacted with an ester such as an acyl halide in the presence of an acid-binding agent to give an N'-acyloxyalkyl derivative, or an w-haloalkyl is reacted with a mono alkali metal glycolate such as mono sodium ethylene glycolate by refluxing in an inert solvent such as benzene or toluene to give an N'-hydroxyalkoxyalkyl derivative.

The primary IO-(aminoalkyl)-trifiuoromethoxyand trifluoromethylmercaptophenothiazines are alternatively produced by reacting the 10-unsubstituted phenothiazine with an excess of acrylonitrile or in an inert solvent such as benzene in the presence of a catalytic amount of a strong base, such as a quaternary base, for instance benzyltrimethylammonium hydroxide. The resulting B-cyanoethyl compound is then reduced, for instance with lithium aluminum hydride to give the primary amine or catalytically with palladium on charcoal as a catalyst. Further alkylation by methods discussed herebefore of the primary amine gives other compounds of this invention.

The IO-(dialkylaminoalkyl)-trifluoromethoxyand trifluoromethylmercaptophenothiazines of this invention may be advantageously prepared from substituted diphenyl sulfides in an alternative kylating the substituted 2-halo-2-amine-diphenyl sulfide prior to the cyclization, thereby substituting the primary amine with a dialkylaminoalkyl moiety which is not reactive under the cyclization conditions subsequently employed. The conditions for the alkylation and cyclization steps are identical to those described above for the 10-alkylation of the substituted phenothiazines and the cyclization of the substituted diphenyl sulfides, respectively.

The foregoing is a general description of the main synthetic routes in the preparation of 10-(w-dialkylaminoalkyl)-trifiuoromethoxyand trifluoromethylmercaptophenothiazine derivatives. It will be readily apparent to one skilled in the art that variations of these procedures are possible. Of particular advantage as a preparative procedure is the method thoroughly discussed above, namely, N-alkylation of trifluoromethoxyand trifluoromethylmercaptophenothiazines in the 10-position of the nucleus by a reactive dialkylaminoalkyl ester.

It will be readily apparent to one skilled in the art that manner, namely, by alcertain of the compounds of this invention, notably those in which A is represented by an aliphatic carbon chain branched so that an asymmetric carbon atom is formed may be present as optical isomers. The connotation of the general formulae presented herein is to include all isomers, particularly the separated d or 1 optical isomers as well as the dl mixture of these isomers. If desired, the isomers may be separated for individual use by separation methods known to the art, such as fractional crystallization, for instance, of the d-tartrate salts of the IO-dialkylaminoalkylated trifiuoromethoxyand trifiuoromethylmercaptophenothiazine derivatives. Alternatively, a synthesis starting with an optically active side chain may yield the desired optical isomer.

The following examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation and will serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof respectively.

Example 1 To a solution of 284.5 g. of 3-bromophenyl methyl sulfide in 1425 ml. of dry chloroform at 10 0, dry chlorine is introduced while the solution is irradiated with a 150 watt lamp. The reaction mixture is maintained at 1518 C. for six and one-half hours. The reaction is stopped and a vigorous stream of nitrogen is introduced. The solvent is removed under reduced pressure and the residue distilled to give a yellow oil, 3-brornophenyl trichloromethyl sulfide, B.P. 102104 C./ 1.1 mm.

A mixture of 142.0 g. of S-bromophenyl trichloromethyl sulfide and 110.0 g. of antimony trifiuoride is heated in a distillation flask and the fraction boiling at 190-205" C. is collected. This fraction is dissolved in 800 ml. of ether and washed several times with 6 N hydrochloric acid and then water. The ether solution is dried and the solvent removed under reduced pressure. Distillation at atmospheric pressure yields a colorless liquid, 3-bromophenyl trifluoromethyl sulfide, B.P. 192 194 C.

A mixture of 160.0 g. of 3-bromophenyl trifluoromethyl sulfide, 100.0 g. of acetanilide, 52.9 g. of anhydrous potassium carbonate and 2.1 g. of copper-bronze powder is heated in an oil bath at a bath temperature of 220230 C. for 24 hours. The cooled dark brown viscous mass is extracted with 750 ml. of acetone and the solvent removed under reduced pressure. To the dark brown residue, 180 ml. of concentrated hydrochloric acid in 515 ml. of ethanol is added. The mixture is refiuxed for five hours and allowed to stand at room temperature over night. It is then poured into 2.5 liters of cold water and made just alkaline with 20% sodium hydroxide. Extraction with ether and removal of the dried solvent under reduced pressure gives a dark residue which is vacuum distilled to yield a pale yellow oil, 3-trifiuoromethylmercaptodiphenyl amine, B.P. -119 C./ 0.3 mm.

A mixture of 117.0 g. of 3-trifiuoromethylrnercaptodiphenyl amine, 25.0 g. of sulfur and 1.8 g. of iodine is heated in an oil bath at -160 C. for one and on half hours under a stream of nitrogen. The cooled reaction mass is dissolved in one liter of boiling benzene and treated with chromatographic alumina and charcoal. Concentration of the filtrate gives a solid, Z-trifiuoromethylmercaptophenothiazine, which recrystallizes from carbon tetrachloride as yellow plates, M.P. -166 C Example 2 to 25.7 g. of 3-nitro-4-chlorophenyl trifiuoromethyl sulfide dissolved in 125 ml. of ethanol. The resulting mixture is refluxed for three hours and filtered while hot. The solid removed by filtration is washed several times with hot ethanol. Diluting the combined ethanolic solutions with water and cooling yields 2'-bromo-2-nitro-4- trifluoromethylmercaptodiphenyl sulfide.

A solution of 338.0 g. of stannous chloride crystals in 1 1. of concentrated hydrochloric acid is mixed carefully with 61.4 g. of 2-bromo-2-nitro-4-trifluoromethylmercaptodiphenyl sulfide. The mixture is stirred and heated at reflux for five hours, cooled and filtered. The solid metal complex is refluxed for one hour with 10% sodium hydroxide solution and then washed with benzene. The organic layer is removed and the residue Washed several times With benzene. The combined benzene washers are evaporated in vacuo to yield after purification, 2-bromo-2-amino-4-trifluoromethylmercaptodiphenyl sulfide.

A suspension of 19.0 g. of 2-bromo-2-arnino-4-trifiuoromethylrnercaptodiphenyl sulfide and 2.0 g. of sodium amide in 400 ml. of dry toluene is stirred and refluxed for 30 minutes. A solution of 8.5 g. of 3-chlorol-dimethylaminopropane in 50 ml. of toluene is added and the mixture refluxed for six hours. After cooling, the reaction mixture is quenched in 200 ml. of ice water. The organic layer is separated, subsequently added to several benzene washes and the combined solution extracted with dilute hydrochloric acid. The acidic extracts are neutralized with sodium hydroxide solution and extracted with ether. Removal of the dried solvent in vacuo gives 2 bromo 2 (3" dirnethylaminopropylamino)-4-trifluoromethylmercaptodiphenyl sulfide.

Example 3 A suspension of 38.0 g. of 2'-bromo-2-amino-4-trifluoromethylmercaptodiphenyl sulfide (prepared as in Example 2), 15.9 g. of anhydrous potassium carbonate and 0.8 g. of copper-bronze powder in 400 ml. of dimethylformamide is stirred and heated at reflux for 18 hours. After cooling, the reaction mixture is filtered and the filtrate diluted with water to give the solid Z-trifluoromethylmercaptophenothiazine.

Example 5 A mixture of 3.0 g. of Z-trifluoromethylmercaptophenothiazine (prepared as in Example 4), 0.41 g. of sodium amide and 50 ml. of Xylene is stirred and heated at reflux for 20 minutes. A solution of 1.9 g. of 1-(3-chloropropyl)-4-methylpiperazine in ml. of xylene is added and the mixture refluxed for four hours. The cooled reaction mixture is treated with water, extracted with dilute hydrochloric acid and the acid extracts neutralized with aqueous ammonia. Benzene extraction and subsequent removal of the dried solvent in vacuo yields 10-[3'-(4-methyl-1- piperazinyl)propyl] 2 trifluoromethylmercaptophenothiazine.

An ethereal solution of the free base is treated with ethereal hydrogen chloride to give the dihydrochloride salt.

Example 6 A suspension of 14.9 g. of 2-trifluoromethylmercaptophenothiazine (prepared as in Example 4), 2.1 g. of sodamide and 12.7 g. of 3-chloro-1-(1',2',3',5',6'-pentameth- 'for 30 minutes.

ylpiperazinyl)-propane in 450 ml. of toluene is heated at reflux for four hours. After treating the reaction mixture with water, the separated organic layer is extracted with dilute hydrochloric acid. The combined acid extracts are neutralized with ammonium hydroxide and extracted with benzene. The solvent is removed to give the residual 10-[3-(1,2",3",5"6"-pentamethylpiperazinyl)- propyl] 2 trifluoromethylmercaptophenothiazine. The free base is reacted with maleic acid in ethyl acetate to furnish the dimaleate salt.

Example 7 A mixture of 15.7 g. of nitric acid and 24.5 g. of sulfuric acid, cooled to 0 C., is added slowly to 8.8 g. of 4-aminophenyl trifluoromethyl ether. The mixture is stirred for three hours at 5 C. and then poured onto ice. The solid is filtered, washed with Water and recrystallized from ethanol to yield 3-nitro-4-aminophenyl trifluoromethyl ether.

Following the general Sandmeyer procedure, 3-nitro-4- aminophenyl trifluoromethyl ether is diazotized in hydrochloric acid with sodium nitrite at 0 C. and a solution of one equilavent of cuprous chloride in hydrochloric acid is added. The complex is decomposed in the usual manner by warming a suspension of this substance and the oily layer which separates is steam distilled to give 3-nitro-4-chlorophenyl trifluoromethyl ether.

A solution of 2.0 g. of sodium hydroxide pellets in 15 ml. of water is added to a solution of 9.5 g. of 2-bromothiophenol in 125 ml. of ethanol and the mixture added to 12.1 g. of 3-nitro-4-chlorophenyl trifluoromethyl ether dissolved in 75 ml. of ethanol. The resulting mixture is heated at reflux for three hours and filtered while hot. The solid removed by filtration is washed several times with hot ethanol. Diluting the combined ethanolic solutions with water and cooling furnishes 2-bromo-2-nitro-4- trifluoromethoxydiphenyl sulfide.

A solution of 225.7 g. of stannous chloride crystals in 750 ml. of concentrated hydrochloric acid is mixed with 39.4 g. of 2-bromo-2-nitro-4-trifluoromethoxydiphenyl sulfide. The mixture is stirred and refluxed for five hours, cooled and filtered. The complex is refluxed for one hour with 10% sodium hydroxide solution and then washed with benzene. The organic layer is removed and the reisdue Washed several times with benzene. The combined benzene washes are evaporated in vacuo to yield after purification, 2'-bromo-2-amino-4-trifluoromethoxydiphenyl sulfide.

A suspension of 36.4 g. of 2-bromo-2-amino-4-trifluoromethoxydiphenyl sulfide, 15.9 g. of anhydrous potassium carbonate and 1.5 g. of copper-bronze powder in 300 ml. of dimethyl formamide is flushed with nitrogen and refluxed with stirring for 18 hours under a stream of nitrogen. The cooled reaction mixture is filtered and quenched in 1 l. of water. The solid thus obtained is purified by recrystallization and sublimation to give crystals of 2-trifiuoromethoxyphenothiazine.

Example 8 A suspension of 14.2 g. of 2-trifluoromethoxyphenothiazine (prepared as in Example 7), and 1.2 g. of lithium amide in ml. of dry xylene in refluxed, with stirring,

A solution of 6.7 g. of 3-chloro-1-dimethylaminopropane in 20 ml. of xylene is added slowly and the mixture refluxed for three hours. The cooled reaction mixture is treated with water, extracted with dilute hydrochloric acid and the acid extracts neutralized with aqueous ammonia. After benzene extraction and subsequent removal of the dried solvent in vacuo, the crude product, 10-(3-dimethylaminopropyl)-2-trifluoromethoxyphenothiazine, is obtained.

A solution of 1.0 g. of the base in 75 ml. of ether is treated with an ethereal solution of hydrogen chloride to yield, after cooling and concentration, the hydrochloride salt.

9 Example 9 A mixture of 14.2 g. of 2-trifluoromethoxyphenothiazine (prepared as in Example 7), 1.2 g. of lithium amide and 200 ml. of xylene is stirred and refluxed for 20 minutes. A solution of 9.7 of 1-(3-chloropropyl)-4-methylpiper'azine in 100 ml. of xylene is added and the mixture is refluxed for five hours. Working up the reaction mixture as in Example 8, gives the product, lO -[3-(4"-methyl-1"- pi perazinyl) -propyl] -2-trifluoromethoxyphenothiazine.

The free base (1.0 g.) dissolved in 100 ml. of ether is treated with an excess of ethereal hydrogen chloride to give the dihydrochloride salt.

Example 10 A mixture of 14.2 g. of 2-trifluoromethoxyphenothiazine (made as in Example 7), 2.1 g. of sodium amide and 8.2 g. of 2-chloro-l-morpholinylethane in 200 ml. of dry benzene is stirred at room temperature in an atmosphere of nitrogen for 15 hours and then heated at reflux for three hours. The cooled reaction mixture is treated with Water, extracted with dilute mineral acid and the acid extracts neutralized with sodium hydroxide solution. Extraction with benzene and removal of the dried solvent gives the product, l-(2-N-morpholinylethyl)-2-trifiuoromethoxyphenothiazine.

Example 1] A mixture of 5.7 g. of 2-trifluoromethoxyphenothiazine (made as in Example 7), 0.8 g. of sodium amide and 5.1 g. of 3-ch1oro-1- 1'-methyl-2,5-diethylpiperazinyl) -propane in 200 ml. of toluene is heated at reflux for four hours. The reaction mixture is worked up as described in Example 10 to give l0-[3-(l"-methyl-Z",5"-diethylpiperazinyl) -propyl] -2-triflu oromethoxyphenothiazine.

Example 12 A solution of 8.0 g. of lithium aluminum hydride in 250 ml. of ether is added slowly to a stirred suspension of 16.8 g. of l0-(2'-cyanoethyl)-2-trifluoromethoxyphenothiazine (prepared by reacting 2-trifluoromethoxyphenothiazine, made as in Example 7, with acrylonitrile in the presence of benzyltrirnethylammonium hydroxide in 500 ml. of anhydrous ether). Theresulting mixture is refluxed for eight hours. The cooled reaction mixture is treated with methanol to destroy the metal complex, filtered and the filtrate evaporated. The residue is extracted with dilute hydrochloric acid, the acid extracts neutralized and then extracted with chloroform. Removal of the solvent in vacuo yields the product, 10-(3'-aminopropyl)-2-trifluoromethoxyphenothiazine.

Example 13 A solution of 5.1 g. of 10-(3'-hydroxypropyl)-2-trifluoromethylmercaptophenothiazine p-toluenesulfonate (prepared by reacting the sodio derivative of Z-trifiuoromethylmercaptophenothiazine with *y-bI'OIIlOPIOPYltGiIdhydropyranyl ether, hydrolyzing the pyranyl group with hydrochloric acid and acylating the 'y-hydroxy compound with excess p-toluenesulfonyl chloride in pyridine) and 2.9 g. of butylamine in 30 ml. of ethanol is heated at reflux for ten hours. The solvent is evaporated and the residue extracted with a Water-chloroform mixture. The organic layer is separated, extracted with dilute hydrochloric acid and the acid extracts neutralized with sodium carbonate solution. The product is extracted into ethyl acetate and treated with maleic acid to form 10-(3-butylaminopropyl) 2 trifluoromethylmercaptophenothiazine maleate.

Following this procedure, using an excess of methylamine in a sealed tube, 10 -(3-methylaminopropyl)-2-trifluoromethylmercaptophenothiazine is prepared.

Example 14 A suspension of 7.5 g. of 2-trifluoromethylmercaptophenothiazine (made as in Example 4), 8.0 g. of N-carbobenzoxy-N'-(3-cloropropyl)-piperazine (obtained by re acting N-carbobenzoxypiperazine with 3-bromopropyl chloride) and 1.0 g. of sodamide in ml. of toluene is heated at reflux for four hours. Working up the reaction mixture as in Example 5 yields l0-[3'-(N-carbobenzoxypiperazinyD-propyl] 2 trifluoromethylmercaptophenothiazine.

A solution of 44.7 g. of the free base in 400 ml. of aqueous ethanol and 20 ml. of 40% sodium hydroxide solution is heated at reflux for four hours. The solvent is removed in vacuo and the residue treated with benzene and water. The dried organic layer is evaporated to give the product, 10-(3-piperazinylpropyl)-2-trifluoromethylmercaptophenothiazine.

Example 15 One equivalent of ethylene oxide is added to a solution of 9.8 g. of 10-(3-piperazinylpropyl)-2-trifluoromethylmercaptophenothiazine (prepared as in Example 14) in 50 ml. of methanol and the mixture heated at reflux for one and one-half hours. The solvent is removed in vacuo and 3.0 g. of benzoyl chloride in 20 ml. of benzene is added to a benzene solution of the residual hydroxyethyl compound. This mixture is refluxed for 20 minutes and solvents are removed in vacuo to give 10-[3-(N-benzoyloxyethylpiperazinyl) propyl]-2-trifiuoromethylmercaptophenothiazine hydrochloride. Treating an alcoholic solution of the hydrochloride with isopropanolic hydrogen chloride yields the dihydrochloride salt.

Similarly, acylating the 10-[3'(N-hydroxyethylpiperazinyl) propyl]-2-trifluoromethylmercaptophenothiazine (prepared as described above) with acetyl chloride furnishes the 10-[3'-(N-acetoxyethylpiperazinyl)-propyl]- 2 trifluoromethylmercaptophenothiazine hydrochloride which may be converted to the dihydrochloride salt as above.

Example 16 A susupension of 8.5 g. of 10-(3'-piperazinylpropyl)-2- trifiuoromethylmercaptophenothiazine (made as in Example 14), 3.4 g. of w-bromobutanol and 8.0 g. of potassium carbonate in 200 ml. of xylene is stirred and heated at refiuxe for five hours. After the addition of water to the reaction mixture, the separated xylene layer is extracted with dilute mineral acid. The acid extracts are neutralized and extracted With benzene. Distilling the solvent in vacuo leaves the residual product, 10-[3-(N-w-hydroxybutylpiperazinyl)-propyl] 2 trifluoromethylmercapto phenothiazine.

A solution of 4.8 g. of the free base in 75 ml. of ben zene is treated with 2.1 ml. of butyryl chloride. After standing at room temperature for 12 hours, the reaction mixture is poured into Water, neutralized and extracted with benzene. Evaporation of the solvent leaves a residue which is dissolved in alcohol and reacted with anhydrous hydrogen chloride gas thus yielding the dihydrochloride of 10-[3-(N-w-butyryloxybutylpiperazinyl)-propyl] 2 trifluorornethylmercaptophenothiazine.

Example 17 To a solution of 4.2 g. of 10-(3-piperazinylpropyl)-2- trifiuoromethylmercaptophenothiazine (made as in Example 14) in 300 ml. of benzene is added 1.7 g. of phenylacetyl chloride, slowly, with stirring. The reaction mixture is allowed to stand at room temperature for 15 hours and then filtered to obtain the product, 10-[3'-N-phenylacetylpiperazinyl)-propyl] 2 trifluoromethylmercaptophenothiazine hydrochloride.

Example 18 A suspension of 14.2 g. of 2-trifiuoromethoxyphenothiazine (prepared as in Example 7), 2.1 g. of sodamide and 14.4 g. of N-diethy1carbamyl-N'-('y-chloropropyD- piperazine in ml. of xylene is heated at reflux for six hours. After treating the reaction mixture with water, the separated organic layer is extracted with dilute hy- Example 19 A mixture of 7.1 g. of 2-trifluoromethoxyphenothiazine (prepared as in Example 7), 1.1 g. of sodamide and 5.7 g. of 6-bromo-l-dimethylaminohexane in 100 ml. of dryxylene is refluxed for 40 hours. Treating the reaction mixture as in Example 8 gives 10-(6'-dirnethylaminohexyl) -Z-trifluoromethoxyphenothiazine.

Example 20 A suspension of 14.2 g. of 2-trifluoromethoxyphenothiazine (prepared as in Example 7) and 2.1 g. of sodamide in 100 ml. of toluene is stirred while a solution of 11.3 g. of 3-boromo-Z-piperidylpropane in 100 ml. of toluene is added slowly at 100 C. The mixture is refluxed for three hours, cooled and treated with water. The separated organic layer is extracted with acid, neutralized with dilute aqueous ammonia and further extracted with benzene. Removal of the solvent in vacuo gives 10-(3'- N-piperidylpropyl -2-trifluoromethoxyphenothiazine.

Example 21 A mixture of 3.0 g. of 2-trifluoromethylmercaptophenothiazine (prepared as in Example 1), 0.5 g. of sodium amide and 50 ml. of xylene is refluxed while 3.0 g. of 3-brorno-l-pyrrolidinylpropane hydrobromide is slowly added. The resulting mixture is stirred and refluxed for 12 hours. Treating the reaction mixture as described in Example 20, 10-(3-N-pyrrolidinylpropyl) 2 trifluoromethylmercaptophenothiazine is obtained.

Example 22 A suspension of 14.2 g. of 2-trifluoromethoxyphenothiazine (made as in Example 7), 2.1 g. of sodamide and 9.8 g. of 3-chloro-1- (N-thiomoropholinyl)-propane in 100 ml. of xylene is heated at reflux for 12 hours. Working up the reaction mixture as outlined in Example 20 results in the isolation of 10-[3'-(N-thiomorpholinyl)-propyl]-2- trifluoromethoxyphenothiazine.

Example 23 A stirred suspension of 8.5 g. of l-(3-piperazinylpropyl)-2-trifluoromethylmercaptophenothiazine (made as in Example 14), 0.8 g. of sodamide and 4.0 g. of 2- bromo-l-diethylaminoethane in 100 ml. of benzene is heated at reflux for six hours. Treating the reaction mixture as described in Example 6 gives -[3-(N-;3-diethylaminoethylpiperazinyl) propyl] 2-trifluoromethylmercaptophenothiazine.

Example 24 Example 25 A mixture of 4.3 g. of 10-(3-piperazinylpropyl)-2-trifluoromethylmercaptophenothiazine (made as in Example 14) and 1.4 g. of nicotinic acid chloride in 50 ml. of benzene is heated at reflux for three hours. The separated solid is 10-[3'-(N-nicotinoylpiperazinyl)-propyl]- 2-trifluoromethylmercaptophenothiazine hydrochloride.

12 Example 26 A mixture of 14.2 g. of 2-trifluoromethoxyphenothiazine (prepared as in Example 7), 2.1 g. of sodium amide and 13.6 g. of N-carbethoxy-N-(a-chloro-fi-methylpropyl)-piperazine (obtained from the reaction of N-carbethoxypiperazine and 3-bromo-2-methylpropyl chloride) in 300 ml. of toluene is refluxed for four hours. Following the work-up procedure of Example 20, 10-[3-N-car bethoxypiperazinyl) 2 methylpropyl] 2 trifluoromethoxyphenothiazine is obtained.

Example 27 A solution of 5.0 g. of 10-[3-(N-carbethoxypiperazinyl) 2' methylpropyl] 2 trifluoromethoxyphenothiazine (prepared as in Example 26) in ml. of aqueous ethanol and 5 ml. of 40% sodium hydroxide solution is heated at reflux for four hours. The solvent is removed in vacuo and the residue treated with benzene and water. Evaporation of the dried solvent, yields 10-(2'- methyl-3-piperazinylpropyl) 2 trifluoromethoxyphenothiazine.

An ethanolic solution of mandelic acid is added to a solution of the free base (1.0 g.) in 100 ml. of ethyl acetate. Concentration and cooling gives l0-(2-methyl- 3'-piperazinylpropyl)-2-trifluoromethoxyphenothiazine dimandelate.

Example 28 To a solution of 8.5 g. of 10-(2'-methyl-3'-piperazinylpropyl) 2 trifluoromethoxyphenothiazine (made as in Example 27) in 100 ml. of ethanol is added 0.9 g. of ethylene oxide. The resulting mixture is refluxed for two hours. The residue hydroxyethyl compounds, after removal of the solvent, is dissolved in ml. of benzene and 2.0 g. of acetyl chloride in 25 ml. of benzene is added. The resulting mixture is heated at reflux for 30 minutes, cooled and all solvents removed in vacuo to give the residual monohydrochloride salt of 10-[2'-methyl 3 (N acetoxyethylpiperazinyl) propyl] 2 trifluoromethoxyphenothiazine. This is dissolved in alcohol and treated with isopropanolic hydrogen chloride to yield the dihydrochloride salt.

Example 29 To a mixture of 8.5 g. of 10-(2-methyl-3'-piperazinylpropyl) -2-trifluoromethoxyphenothiazine (made as in Example 27) and 50 ml. of 85% formic acid solution, warmed to 50 C., is slowly added 15 ml. of 37% formalin solution. When there is no further evolution of carbon monoxide, the reaction mixture is cooled, neutralized and extracted with benzene. Evaporation of the solvent leaves the residual product, 10-[3-(4-methyl- 1-piperazinyl)-2methylpropyl] 2 trifluoromethoxyphenothiazine.

Example 30 A mixture of 14.2 g. of 2-trifluoromethoxyphenothiazine (prepared as in Example 7), 2.1 g. of sodium amide and 13.9 g. of 3-chloro-1-(N-benzylpiperazinyl)- propane in ml. of toluene is refluxed for eight hours. Following the work-up procedure of Example 8, 10-[3'- (N-benzylpiperazinyl)-propyl] 2 trifluoromethoxyphenothiazine is isolated. The free base (1.0 g.) is reacted with an excess of maleic acid in ethyl acetate. Cooling and concentration gives the dimaleate salt.

Similarly, by using 16.1 g. of 3-chloro-1-(N-w-phenylbutylpiperazinyl)-propane, 10-[3-(Nw phenylbutylpiperazinyl)-propyl]-2 trifluoromethoxyphenothiazine is obtained.

Example 31 with water and evaporated. A solution of the residue 13 in alcohol is reacted with one equivalent of hydrochloric acid to yield l-[3-(N-acetylpiperazinyl)-propyl]-2-trifluoromethylmercaptophenothiazine hydrochloride.

Example 32 A mixture of 4.2 g. of 10-(3'-piperazinylpropy1)-2-trifluoromethylmercaptophenothiazine (made as in Example 14) dissolved in 150 ml. of benzene and 3.0 g. of benzoyl chloride is heated at reflux for three hours. Concentrating the reaction mixture yields the solid product, 10-[3-(N-benzoylpiperazinyl)-propyl]-2 trifluoromethylmercaptophenothiazine hydrochloride.

Example 33 A solution of 8.4 g. of 10-(3'-piperazinylpropyl)-2- trifluoromethylmercaptophenothiazine (prepared as in Example 14) in 500 ml. of benzene and 5.0 g. of butyryl chloride is refluxed for three hours. Concentration of the reaction mixture gives the hydrochloride of 10-[3'- (N-butyrylpiperazinyl)-propyl] 2 trifluoromethylmercaptophenothiazine.

Following the procedure described above and acylating with cyclopentylpropionyl chloride results in the preparation of 10-[3'-(N-cyclopentylpropionylpiperazinyl)- propyl]-2-trifluoromethylmercaptophenotbiazine.

Example 34 A suspension of 8.5 g. of 10-(3'-piperazinylpropyl)- 2-trifluoromethylmercaptophenothiazine (made as in Example 14), 4.0 g. of 2-bromo-2'-hydroxyethyl ether and 4.0 g. of potassium carbonate in 150 ml. of toluene is refluxed for six hours. The reaction mixture is treated with water, the organic layer treated with acid, made baisc and re-extracted. Evaporation of the extracts yields 10 [3' (N-hydroxyethoxyethylpiperazinyl)-propyl]-2- trifluoromethylmercaptophenothiazine.

Example 35 A stirred suspension of 9.4 g. of 10-(3'-piperazinylpropyl)-2 trifluoromethylmercaptophenothiazine (made as in Example 14), 0.9 g. of sodamide and 4.6 g. of 2-bromoethyl cyclohexane in 125 ml. of xylene is refluxed for eight hour Working up as in Example 6, 10-[3'-(N 13 cyclohexylethylpiperazinyl)-propyl] -2-trifluoromethylmercaptophenothiazine is obtained.

Example 36 A suspension of 4.3 g. of 10-(3'-piperazinylpropyl)- 2-trifluoromethylmercaptophenothiazine (made as in Example 14), 3.4 g. of 4-bromo-4'-hydroxybutyl ether (prepared by the careful treatment of 4,4'-dihydroxybutyl ether with one equivalent of hydrobromic acid) and 2.8 g. of potassium carbonate in 150 ml. of xylene is re fiuxed for 24 hours. Upon working up the reaction mixture as in Example 34, 10-[3'-(N-hydroxybutoxybutylpiperazinyl)-propyl] 2 trifluoromethylmercaptopheno thiazine is obtained.

This application is a continuation-in-part of application Serial No. 666,480 filed June 18, 1957, now abandoned.

What is claimed is:

1. Chemical compounds selected from the group consisting of a free base of the formula:

--YOFa 8 2 sisting of oxygen and sulfur; A is an alkylene chain having 2 to 6 carbon atoms separating the nitrogens to which it is attached by "at least 2 carbon atoms; and' R and R are members selected from the group consisting of hydrogen, alkyl and, when taken together with the nitrogen to which they are attached, a member selected from the group consisting of pyrrolidinyl, piperdinyl, morpholinyl, thiomorphol-inyl, N-hydro gen piperazinyl,

-alkylpiperazinyl, N-(w-hydroxyalkylene)-piperazinyl, N-(w-alkanoyloxyalkylene)-piperazinyl, N (av-benzoyloxyalkyl-ene)piperazinyl, N (w-dialkylaminoalkylene)- piperazinyl, N (w-hydroxyalkyleneoxyalkylene)-piperazinyl, N-phenylalkyl piperazinyl, N-alkanoyl piperazinyl, N-carbethoxy piperazinyl, N-dialkylcarbamyl piperazinyl and N,2,3,5,6-pentamethylpiperazinyl; each of the said alkyl moieties having 1 to 6 carbon atoms and each of the said alkylene and alkanoyl moieties having 2 to 6 carbon atoms and its nontoxic acid addition salts.

2. Chemical compounds of the formula:

in which Y is a member selected from sisting of oxygen and sulfur.

3. A chemical compound of the formula:

4 A chemical compound of the formula:

\ -OOFa 5. A chemical compound of the formula:

\N/ SCF:

JHzCHgOHgN(CH3)g 6. A chemical compound of the formula:

N OOF CHgOHgCHg-N(OH3) a 7. A chemical compound of the formula:

the group con- 8. A chemical compound of the formula:

in which the alkylene moiety has 2 to 6 carbon atoms.

15 l. 15, 10. A chemical compound of the formula: 14. A chemical compound of the formula:

N/ son I 11. A chemical compound of the formula: CH3

References Cited in the file of this patent UNITED STATES PATENTS 3 E ,O H,CH, H, 2,837,518 Jacob et a1. June 3, 1958 15 2,889,322 Jacob et a1 June 2, 1959 12. A chemical compound of the formula: 2 Craig 1959 S 2,919,272 Craig Dec. 29, 1959 2,921,069 Ullyot Jan. 12, 1960 2,928,767 Gulesich et a1 Mar. 15, 1960 so F, 2,944,054 Gordon July 5, 1960 N 2,945,030 Gordon July 12, 1960 iJH CHzCHg-N N-alkylene-oxy-alkylene-hydroxy FOREIGN PATENTS LntOYnhSmh each of the alkylcne moieties has 2 to 6 carbon 25 568,701 Belgium July 15 1958 13. Aschemical compound of the formula. OTHER REFERENCES Conant: The Chemistry of Organic Compounds, revised edition, 1939, page 264. SCF3 30 Lowy et al.: An Introduction to Organic Chemistry,

6th edition, 1945, page 213, chapter XVIII. C 1 I 1CH1N NOH:CH2O 3 z- Brewster: Organic Chemistry, 2d edition (1953), pages 

1. CHEMICAL COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF A FREE BASE OF THE FORMULA: 